JAMA current issue

Context  The optimal unfractionated heparin regimen for percutaneous coronary intervention (PCI) in patients with non–ST-segment elevation acute coronary syndromes treated with fondaparinux is uncertain.

Objective  To compare the safety of 2 unfractionated heparin regimens during PCI in high-risk patients with non–ST-segment elevation acute coronary syndromes initially treated with fondaparinux.

Design, Setting, and Participants  Double-blind randomized parallel-group trial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non–ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010.

Interventions  Patients received intravenously either low-dose unfractionated heparin, 50 U/kg, regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT).

Main Outcome Measures  Composite of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI. Key secondary outcomes include composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30.

Results  The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16-0.97; P = .04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15).

Conclusion  Low-dose compared with standard-dose unfractionated heparin did not reduce major peri-PCI bleeding and vascular access-site complications.

Trial Registration  clinicaltrials.gov Identifier: NCT00790907

Context  Clinicians and trialists have difficulty with identifying which patients are highest risk for cardiovascular events. Prior ischemic events, polyvascular disease, and diabetes mellitus have all been identified as predictors of ischemic events, but their comparative contributions to future risk remain unclear.

Objective  To categorize the risk of cardiovascular events in stable outpatients with various initial manifestations of atherothrombosis using simple clinical descriptors.

Design, Setting, and Patients  Outpatients with coronary artery disease, cerebrovascular disease, or peripheral arterial disease or with multiple risk factors for atherothrombosis were enrolled in the global Reduction of Atherothrombosis for Continued Health (REACH) Registry and were followed up for as long as 4 years. Patients from 3647 centers in 29 countries were enrolled between 2003 and 2004 and followed up until 2008. Final database lock was in April 2009.

Main Outcome Measures  Rates of cardiovascular death, myocardial infarction, and stroke.

Results  A total of 45 227 patients with baseline data were included in this 4-year analysis. During the follow-up period, a total of 5481 patients experienced at least 1 event, including 2315 with cardiovascular death, 1228 with myocardial infarction, 1898 with stroke, and 40 with both a myocardial infarction and stroke on the same day. Among patients with atherothrombosis, those with a prior history of ischemic events at baseline (n = 21 890) had the highest rate of subsequent ischemic events (18.3%; 95% confidence interval [CI], 17.4%-19.1%); patients with stable coronary, cerebrovascular, or peripheral artery disease (n = 15 264) had a lower risk (12.2%; 95% CI, 11.4%-12.9%); and patients without established atherothrombosis but with risk factors only (n = 8073) had the lowest risk (9.1%; 95% CI, 8.3%-9.9%) (P < .001 for all comparisons). In addition, in multivariable modeling, the presence of diabetes (hazard ratio [HR], 1.44; 95% CI, 1.36-1.53; P < .001), an ischemic event in the previous year (HR, 1.71; 95% CI, 1.57-1.85; P < .001), and polyvascular disease (HR, 1.99; 95% CI, 1.78-2.24; P < .001) each were associated with a significantly higher risk of the primary end point.

Conclusion  Clinical descriptors can assist clinicians in identifying high-risk patients within the broad range of risk for outpatients with atherothrombosis.

Context  Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer.

Objective  To estimate risk and mortality reduction stratified by mutation and prior cancer status.

Design, Setting, and Participants  Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009.

Main Outcomes Measures  Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality.

Results  No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer–specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]).

Conclusions  Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.

Context  Although preterm delivery is a well-established risk factor for cerebral palsy (CP), preterm deliveries contribute only a minority of affected infants. There is little information on the relation of CP risk to gestational age in the term range, where most CP occurs.

Objective  To determine whether timing of birth in the term and postterm period is associated with risk of CP.

Design, Setting, and Participants  Population-based follow-up study using the Medical Birth Registry of Norway to identify 1 682 441 singleton children born in the years 1967-2001 with a gestational age of 37 through 44 weeks and no congenital anomalies. The cohort was followed up through 2005 by linkage to other national registries.

Main Outcome Measures  Absolute and relative risk of CP for children surviving to at least 4 years of age.

Results  Of the cohort of term and postterm children, 1938 were registered with CP in the National Insurance Scheme. Infants born at 40 weeks had the lowest risk of CP, with a prevalence of 0.99/1000 (95% confidence interval [CI], 0.90-1.08). Risk for CP was higher with earlier or later delivery, with a prevalence at 37 weeks of 1.91/1000 (95% CI, 1.58-2.25) and a relative risk (RR) of 1.9 (95% CI, 1.6-2.4), a prevalence at 38 weeks of 1.25/1000 (95% CI, 1.07-1.42) and an RR of 1.3 (95% CI, 1.1-1.6), a prevalence at 42 weeks of 1.36/1000 (95% CI, 1.19-1.53) and an RR of 1.4 (95% CI, 1.2-1.6), and a prevalence after 42 weeks of 1.44 (95% CI, 1.15-1.72) and an RR of 1.4 (95% CI, 1.1-1.8). These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1000 (95% CI, 0.30-2.04) and the relative risk was 3.7 (95% CI, 1.5-9.1). At 42 weeks the prevalence was 0.85/1000 (95% CI, 0.33-1.38) and the relative risk was 2.4 (95% CI, 1.1-5.3). Adjustment for infant sex, maternal age, and various socioeconomic measures had little effect.

Conclusion  Compared with delivery at 40 weeks' gestation, delivery at 37 or 38 weeks or at 42 weeks or later was associated with an increased risk of CP.

Context  Optimal treatment to postpone functional decline in patients with dementia is not established.

Objective  To test a nonpharmacologic intervention realigning environmental demands with patient capabilities.

Design, Setting, and Participants  Prospective 2-group randomized trial (Care of Persons with Dementia in their Environments [COPE]) involving patients with dementia and family caregivers (community-living dyads) recruited from March 2006 through June 2008 in Pennsylvania.

Interventions  Up to 12 home or telephone contacts over 4 months by health professionals who assessed patient capabilities and deficits; obtained blood and urine samples; and trained families in home safety, simplifying tasks, and stress reduction. Control group caregivers received 3 telephone calls and educational materials.

Main Outcome Measures  Functional dependence, quality of life, frequency of agitated behaviors, and engagement for patients and well-being, confidence using activities, and perceived benefits for caregivers at 4 months.

Results  Of 284 dyads screened, 270 (95%) were eligible and 237 (88%) randomized. Data were collected from 209 dyads (88%) at 4 months and 173 (73%) at 9 months. At 4 months, compared with controls, COPE patients had less functional dependence (adjusted mean difference, 0.24; 95% CI, 0.03-0.44; P = .02; Cohen d = 0.21) and less dependence in instrumental activities of daily living (adjusted mean difference, 0.32; 95% CI, 0.09-0.55; P = .007; Cohen d = 0.43), measured by a 15-item scale modeled after the Functional Independence Measure; COPE patients also had improved engagement (adjusted mean difference, 0.12; 95% CI, 0.07-0.22; P = .03; Cohen d = 0.26), measured by a 5-item scale. COPE caregivers improved in their well-being (adjusted mean difference in Perceived Change Index, 0.22; 95% CI, 0.08-0.36; P = .002; Cohen d = 0.30) and confidence using activities (adjusted mean difference, 0.81; 95% CI, 0.30-1.32; P = .002; Cohen d = 0.54), measured by a 5-item scale. By 4 months, 64 COPE dyads (62.7%) vs 48 control group dyads (44.9%) eliminated 1 or more caregiver-identified problems (21 = 6.72, P = . 01).

Conclusion  Among community-living dyads, a nonpharmacologic biobehavioral environmental intervention compared with control resulted in better outcomes for COPE dyads at 4 months. Although no group differences were observed at 9 months for patients, COPE caregivers perceived greater benefits.

Trial Registration  clinicaltrials.gov Identifier: NCT00259454

Context  For more than 30 years, guidelines for perinatal regionalization have recommended that very low-birth-weight (VLBW) infants be born at highly specialized hospitals, most commonly designated as level III hospitals. Despite these recommendations, some regions continue to have large percentages of VLBW infants born in lower-level hospitals.

Objective  To evaluate published data on associations between hospital level at birth and neonatal or predischarge mortality for VLBW and very preterm (VPT) infants.

Data Sources  Systematic search of published literature (1976–May 2010) in MEDLINE, CINAHL, EMBASE, and PubMed databases and manual searches of reference lists.

Study Selection and Data Extraction  Forty-one publications met a priori inclusion criteria (randomized controlled trial, cohort, and case-control studies measuring neonatal or predischarge mortality among live-born infants ≤1500 g or ≤32 weeks' gestation delivered at a level III vs lower-level facility). Paired reviewers independently assessed publications for inclusion and extracted data using standardized forms. Discrepancies were decided by a third reviewer. Publications were reviewed for quality by 3 authors based on 2 content areas: adjustment for confounding and description of hospital levels. We calculated weighted, combined odds ratios (ORs) using a random-effects model and comparative unadjusted pooled mortality rates.

Data Synthesis  We observed increased odds of death for VLBW infants (38% vs 23%; adjusted OR, 1.62; 95% confidence interval [CI], 1.44-1.83) and VPT infants (15% vs 17%; adjusted OR, 1.55; 95% CI, 1.21-1.98) born outside of level III hospitals. Consistent results were obtained when restricted to higher-quality evidence (mortality in VLBW infants, 36% vs 21%; adjusted OR, 1.60; 95% CI, 1.33-1.92 and in VPT infants, 7% vs 12%; adjusted OR, 1.42; 95% CI, 1.06-1.88) and infants weighing less than 1000 g (59% vs 32%; adjusted OR, 1.80; 95% CI, 1.31-2.46). No significant differences were found through subgroup analysis of study characteristics. Meta-regression by year of publication did not reveal a change over time (slope, 0.00; P = .87).

Conclusion  For VLBW and VPT infants, birth outside of a level III hospital is significantly associated with increased likelihood of neonatal or predischarge death.